Gut Immune Cells That Travel to Brain May Help Resolve MS Disease Relapses

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A particular type of gut microbiota-reactive immune cells, called IgA-producing B-cells, travels to the brain of multiple sclerosis (MS) patients during relapses, where they produce anti-inflammatory molecules, a study shows.

The underlying mechanisms of this event and these cells’ role in MS remain largely unclear, but these findings suggest that specific gut immune cells may help resolve disease relapses in MS. They also expand on the diverse subsets of immune cells that scientists say are likely involved in the disease, either by promoting or suppressing MS-associated processes.

The data also add to existing evidence supporting a link between gut microbiota and inflammatory responses in MS, and “opens up a whole new line of research,” Anne-Katrin Pröbstel, MD, the study’s first author and a former postdoctoral researcher at University of California-San Francisco (UCSF), said in a UCSF press release.

Of note, gut microbiota — a vast community of friendly bacteria, fungi, and viruses that colonize the gastrointestinal tract — helps to maintain a balanced gut function, protect against disease-causing organisms, and influence the host’s immune system and inflammatory responses.

The study, “Gut microbiota–specific IgA+ B cells traffic to the CNS in active multiple sclerosis,” was published in the journal Science Immunology.

A type of immune cell, B-cells produce specific immunoglobulins (Ig), or antibodies — molecules that bind to invasive microorganisms, helping to kill them.

B-cells that produce IgG, a type of antibody, are known to drive the abnormal immune attacks against myelin — the protective sheath that covers nerve fibers — and the neuroinflammation that leads to MS-associated neuronal death in the central nervous system (CNS), comprising the brain and spinal cord.

While MS treatments promoting mild B-cell depletion reduce inflammation in MS patients, those leading to a profound depletion of these cells result in disease exacerbation.

“This highlights the complex and important role of the B cell lineage in the [development] of MS and suggests that at least some plasma cells may potentially play a [protective] role during chronic neuroinflammation,” the researchers wrote.

B-cells producing another type of antibody, called IgA, serve as a critical first line of defense against foreign invaders and are thought to help keep the gut microbiome in check, preventing out-of-control growth.

Increasing evidence shows that gut microbiota-reactive, IgA-producing B-cells (IgA B-cells) also can travel to peripheral organs and may play a role in other extra-intestinal autoimmune diseases. However, the role of IgA and IgA-producing B-cells in MS remains unclear.

Now, an international research team, led by UCSF scientists, analyzed IgA and IgA B-cells in the gut, blood, brain tissue, and cerebrospinal fluid (CSF) — the fluid that bathes the brain and spinal cord. Their analysis compared the finding from MS patients, people with other neurodegenerative diseases, and healthy individuals.

The results showed that CSF IgA levels were significantly higher in MS patients during relapse, compared with those of patients in remission, people with other neurodegenerative conditions, and healthy individuals. Notably, the CSF levels of IgG were not significantly different between MS patients under disease relapse or remission.

Further analyses revealed that during MS relapses, but not during remissions, IgA B-cells traveled through the blood to MS brain lesions, where they produced IL-10, an anti-inflammatory molecule.

“Only at the time of an attack was there an increase in these cells and the antibodies they produce,” said Sergio Baranzini, PhD, the study’s senior author.

“That really caught our attention,” he said.

These IgA B-cells were found not to target myelin but rather specific strains of gut bacteria previously linked to inflammation in MS, highlighting a link between gut and CNS immune responses.

“These findings establish gut microbiota-specific IgA+ cells as a systemic mediator in MS and suggest a critical role of [gut] B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions,” the researchers wrote.

Of note, the work relied heavily on data and biological samples collected through the UCSF EPIC Study, which has followed hundreds of MS patients over 16 years.

“I think UCSF is one of the only places where we could have done this [type of work], because of the access to patient samples that allow us to look at bacteria in the gut, immune cells from the blood, immune cells from the spinal fluid and brain tissue,” Pröbstel said.

“It’s really a unique resource,” she added.

In a separate press release from the National MS Society, Pröbstel also noted that what exactly triggers B-cells migration from the gut to the CNS remains undetermined.

“If we find the trigger for that, we could use it to treat MS,” she said.

The team hypothesized that this migration may reflect the recruitment of a set of immune cells that have the capacity to dampen excessive inflammation. It also might be due to chase-after bacteria — cells that target bacteria — that have leaked from the gut and invaded the CNS.

“Further studies are needed to assess gut leakiness and potential CNS penetration of gut microbiota and to elucidate the mechanisms that facilitate IgA+ B cell recruitment to the CNS,” the researchers wrote.